Low-frequency HIV-1 Drug Resistance in Primary HIV-1 Infection

原发性 HIV-1 感染中的低频 HIV-1 耐药性

• 批准号: 7684440
• 负责人: Joanne Donna Stekler
• 金额: $ 42.95万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7684440
• 关键词: Address; Anti-Retroviral Agents; Antiretroviral drug resistance; Biological Assay; Blood; Caring; Clinic; Clinical; Clinical Trials; Consensus Sequence; Consequences of HIV; Data; Detection; Development; Drug resistance; Enrollment; Failure; Frequencies; Future; Genotype; Guidelines; HIV-1; HIV-1 drug resistance; Infection; Intervention; Investigation; Lead; Ligation; Methods; Minority; Modeling; Mutation; Mutation Detection; Natural History; Oligonucleotides; Pattern; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Pilot Projects; Plasma; Population; Population Dynamics; Population Surveillance; Prevalence; Probability; Public Health; Reaction Time; Reporting; Research Design; Resistance; Risk; Seminal Plasma; Source; Specimen; Surveillance Program; Test Result; Testing; Time; Treatment Protocols; Treatment outcome; United States; Universities; Variant; Viral; Virus; Washington; antiretroviral therapy; clinical care; clinically relevant; cohort; compliance behavior; design; drug resistant virus; experience; fitness; follow-up; genital secretion; mutant; novel; programs; public health relevance; resistance mutation; response; transmission process

DESCRIPTION (provided by applicant): Public health surveillance programs using consensus sequencing (genotyping) estimate that at least one in ten antiretroviral (ARV)-naive persons infected with HIV-1 in the United States acquires drug resistant HIV-1. Guidelines therefore recommend resistance testing at the time of entry into care. However, consensus sequencing cannot detect low-frequency variants at levels below 10-50% of the viral population. The oligonucleotide ligation assay (OLA) is a more-sensitive assay that can detect mutations occurring in as little as 5% of the viral quasi-species. In a pilot study conducted among subjects with primary HIV-1 infection enrolled at the University of Washington Primary Infection Clinic (PIC), consensus sequencing detected transmitted HIV-1 drug resistance in 6% of 100 subjects, and OLA detected low-frequency mutations in 28 (30%) of 94 subjects who did not have mutations identified by consensus sequencing. We propose studies that will use OLA to address questions pertaining to the transmission and subsequent consequences of HIV-1 drug resistance. In Aim #1, we will study ARV-naive PIC subjects to compare the duration of detection ("persistence") and level of detection of transmitted HIV-1 drug resistance over time in peripheral blood mononuclear cells (PBMCs), blood and seminal plasma. In Aim #2, we will study PIC subjects initiating ARV therapy and use OLA to determine whether additional mutations can be detected in PBMCs during successful treatment due to the selection of transmitted low-frequency drug resistance mutations or the development of new mutations. In Aim #3, we will use OLA to compare HIV-1 drug resistance patterns in PIC subjects and their source partners to determine whether HIV-1 drug resistance impacts "transmission fitness". These novel investigations would broaden our understanding of the natural history and clinical impact of low- frequency HIV-1 drug resistance and inform guidelines for the testing and treatment of HIV-infected persons. If more-sensitive HIV-1 drug resistance assays were to be endorsed for clinical care before there is a full understanding of the relevance of low-frequency mutations, the potential increase in the complexity of initial ARV regimens and subsequent reduction in patient adherence could paradoxically increase the prevalence of drug resistance. Finally, empiric data from partner-pairs will generate information on correlates of HIV-1 transmission that could be incorporated into future models of the population dynamics of drug resistance. These models would estimate the overall proportion of HIV-1 drug resistance that is transmitted from ARV- naive source partners with primary HIV-1 infection versus ARV-experienced source partners with established HIV-1 infection. This data could be used to design public health interventions targeted to these populations to reduce the spread of transmitted HIV-1 drug resistance. PUBLIC HEALTH RELEVANCE: These investigations would broaden our understanding of the natural history and clinical impact of low-frequency HIV-1 drug resistance and inform guidelines for the testing and treatment of HIV-infected persons. Empiric data from partner-pairs could also be used to model population dynamics of drug resistance, quantify the proportion of transmitted HIV-1 drug resistance that is from ARV-naive source partners with primary HIV-1 infection, and develop much- needed public health interventions to reduce the spread of HIV-1 drug resistance.

描述(由申请人提供)：公共卫生监测项目使用共识测序(基因分型)估计，在美国，至少十分之一未经抗逆转录病毒(ARV)感染的HIV-1感染者获得抗药性HIV-1。因此，指南建议在进入护理时进行耐药性测试。然而，共识测序无法在低于病毒群体10%-50%的水平上检测到低频变异。寡核苷酸连接试验(OLA)是一种更灵敏的分析方法，可以检测到仅在5%的准病毒物种中发生的突变。在华盛顿大学初级感染诊所(PIC)登记的原发HIV-1感染者中进行的一项试点研究中，共识测序在100名受试者中检测到6%的人传播了HIV-1耐药性，而OLA在94名未经共识测序确定有突变的受试者中，检测到28名(30%)的低频突变。我们建议进行研究，使用OLA来解决与艾滋病毒-1耐药性的传播和后续后果有关的问题。在目标1中，我们将研究ARV-naive PIC受试者，以比较外周血单核细胞(PBMC)、血液和精浆中检测到的传播的HIV-1耐药性的持续时间(“持久性”)和检测水平。在目标2中，我们将研究启动ARV治疗的PIC受试者，并使用OLA来确定在成功的治疗过程中，由于选择传播的低频耐药突变或新突变的发展，是否可以在PBMC中检测到额外的突变。在目标3中，我们将使用OLA来比较PIC受试者和他们的来源伙伴中的HIV-1耐药性模式，以确定HIV-1耐药性是否影响“传播适合性”。这些新颖的调查将扩大我们对低频率艾滋病毒-1耐药性的自然历史和临床影响的了解，并为艾滋病毒感染者的检测和治疗提供指导方针。如果在充分了解低频突变的相关性之前，更敏感的HIV-1耐药性分析被批准用于临床护理，那么最初ARV方案的潜在复杂性增加，以及随后患者依从性的减少，可能会矛盾地增加耐药性的患病率。最后，来自伙伴对的经验性数据将产生有关艾滋病毒-1传播相关因素的信息，这些信息可能被纳入未来耐药人口动态的模型。这些模型将估计从初次感染HIV-1的ARV初生源伙伴传播的HIV-1耐药性与感染HIV-1的有ARV经验的源伙伴之间的总体比例。这些数据可用于设计针对这些人群的公共卫生干预措施，以减少传播的艾滋病毒-1耐药性的传播。公共卫生相关性：这些调查将扩大我们对低频率艾滋病毒-1耐药性的自然历史和临床影响的了解，并为艾滋病毒感染者的检测和治疗提供指导方针。来自伙伴对的经验数据也可以用来模拟抗药性的人口动态，量化来自初次感染艾滋病毒-1的抗逆转录病毒来源的伙伴传播的艾滋病毒-1耐药性的比例，以及制定急需的公共卫生干预措施，以减少艾滋病毒-1耐药性的传播。